Metabolic regulation of <scp>NLRP</scp>3

Hughes, Mark; O’Neill, Luke A. J.

doi:10.1111/imr.12608

Cited by 241 publications

(174 citation statements)

References 89 publications

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“…It has been shown that glycolytic enzymes impact on the inflammasome in macrophages [40]. Hexokinase 1 interacts with voltage-dependent anion channel (VDAC)1 which activates the inflammasome while PKM2 triggers inflammasome activation in a HIF-1α-dependent manner [41] and also activates eukaryotic translation initiation factor 2A kinase, which directly interacts with inflammasome components regulating its assembly [42].…”

Section: Discussionmentioning

confidence: 99%

Anti-TLR2 antibody triggers oxidative phosphorylation in microglia and increases phagocytosis of β-amyloid

Rubio-Araiz

Finucane

Keogh

et al. 2018

J Neuroinflammation

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BackgroundMicroglia are multifunctional cells that are primarily neuroprotective and a deficit in their functional integrity is likely to be a contributory factor in the deteriorating neuronal function that occurs with age and neurodegeneration. One aspect of microglial dysfunction is reduced phagocytosis, and this is believed to contribute to the accumulation of amyloid-β (Aβ) in Alzheimer’s disease (AD). Therefore, improving phagocytosis should be beneficial in limiting the amyloidosis that characterises AD.MethodsHere, we investigated whether an antibody that targets toll-like receptor (TLR)2 might attenuate the inflammatory and metabolic changes induced by lipopolysaccharide (LPS) and amyloid-β. The impact on phagocytosis was assessed by immunohistochemistry. We evaluated the metabolic changes with the SeaHorse Extracellular Flux Analyser and studied the expression of key enzymes driving glycolysis by western blotting. For all experiments, statistical significance was determined by unpaired Student’s t test and two-way analysis of variance (ANOVA).ResultsWe have reported that, when exposed to an inflammatory stimulus, microglia switch their metabolism towards the metabolically- inefficient glycolysis; this potentially impacts on metabolically demanding functions like phagocytosis. Anti-TLR2 antibody increased phagocytosis of Aβ in LPS + Aβ-stimulated microglia and this was linked with the ability of the antibody to attenuate the LPS + Aβ-triggered inflammasome activation. LPS + Aβ increased glycolysis in microglia and increased the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)3, an enzyme that plays a key role in driving glycolysis; these effects were inhibited when cells were incubated with the anti-TLR2 antibody. The data also show that antibody treatment increased oxidative metabolism.ConclusionsThus, microglia with an inflammatory phenotype, specifically cells in which the inflammasome is activated, are glycolytic; this may compromise the metabolic efficiency of microglia and thereby provide an explanation for the reduced phagocytic function of the cells. We propose that, by restoring oxidative metabolism and reducing inflammasome activation in microglia, phagocytic function is also restored.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1281-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Anti-TLR2 antibody triggers oxidative phosphorylation in microglia and increases phagocytosis of β-amyloid

Rubio-Araiz

Finucane

Keogh

et al. 2018

J Neuroinflammation

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“…The inflammasome is a multi‐subunit cytoplasmic complex that catalyzes the proteolytic processing of target substrates via its effector enzyme caspase 1 (Malik and Kanneganti ; Franklin et al . ; Hughes and O'Neill ). In general, the inflammasome is formed by a nucleotide‐binding oligomerization domain‐like receptor (NLR) family member that senses cytoplasmic danger‐associated molecular patterns, the adaptor apoptosis‐associated speck‐like protein containing a carboxy‐terminal CARD (ASC), and pro‐caspase 1 (Lamkanfi and Dixit ) that undergoes autocatalytic cleavage to its active form upon inflammasome assembly (Rathinam and Fitzgerald ).…”

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confidence: 97%

Caspase 1 activity influences juvenile Batten disease (CLN3) pathogenesis

Burkovetskaya

Bosch

Karpuk

et al. 2018

Journal of Neurochemistry

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Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is an autosomal recessive lysosomal storage disease caused by loss-of-function mutations in CLN3. Symptoms appear between 5 and 10 years of age, beginning with blindness and seizures, followed by progressive cognitive and motor decline, and premature death. Glial activation and impaired neuronal activity are early signs of pathology in the Cln3 mouse model of JNCL, whereas neuron death occurs much later in the disease process. We previously reported that Cln3 microglia are primed toward a pro-inflammatory phenotype typified by exaggerated caspase 1 inflammasome activation and here we extend those findings to demonstrate heightened caspase activity in the Cln3 mouse brain. Based on the ability of caspase 1 to cleave a large number of substrates that have been implicated in JNCL pathology, we examined the functional implications of caspase 1 inflammasome activity by crossing Cln3 and caspase 1-deficient mice to create Cln3 /Casp-1 animals. Caspase 1 deletion influenced motor behavior deficits and astrocyte activation in the context of CLN3 mutation, since both were significantly reversed in Cln3 /Casp-1 mice, with phenotypes approaching that of wild-type animals. We also report a progressive age-dependent reduction in whisker length in Cln3 mice that was partially caspase 1-dependent. However, not all CLN3 phenotypes were reversed following caspase 1 deletion, since no significant differences in lysosomal accumulation or microglial activation were observed between Cln3 and Cln3 /Casp-1 mice. Although the molecular targets of aberrant caspase 1 activity in the context of CLN3 mutation remain to be identified, our studies suggest that caspase 1 may represent a potential therapeutic target to mitigate some attributes of CLN3 disease. This article is part of the Special Issue "Lysosomal Storage Disorders".

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“…Nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3 or NALP3) is a cytoplasmic sensor that oligomerizes to form a platform known as inflammasome, a protein complex that controls the release of IL-1β and IL-18 by activating caspase-1 [9]. In macrophages, NLRP3 inflammasome activation can be triggered by the pore-forming ionophore nigericin, extracellular ATP, and crystalline substances that induce pyroptosis, a type of cell death [10]. In addition, previous research has shown that some fatty acid-derived lipids, such as the prostaglandin E 2 (PGE 2 ), regulates NLRP3 and the maturation of IL-1β.…”

Section: Introductionmentioning

confidence: 99%

Annexin A1 Regulates NLRP3 Inflammasome Activation and Modifies Lipid Release Profile in Isolated Peritoneal Macrophages

Sanches

Branco

Duarte

et al. 2020

Cells

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Annexin A1 (AnxA1) is a potent anti-inflammatory protein that downregulates proinflammatory cytokine release. This study evaluated the role of AnxA1 in the regulation of NLRP3 inflammasome activation and lipid release by starch-elicited murine peritoneal macrophages. C57bl/6 wild-type (WT) and AnxA1-null (AnxA1 -/-) mice received an intraperitoneal injection of 1.5% starch solution for macrophage recruitment. NLRP3 was activated by priming cells with lipopolysaccharide for 3 h, followed by nigericin (1 h) or ATP (30 min) incubation. As expected, nigericin and ATP administration decreased elicited peritoneal macrophage viability and induced IL-1β release, more pronounced in the AnxA1 -/cells than in the control peritoneal macrophages. In addition, nigericin-activated AnxA1 -/macrophages showed increased levels of NLRP3, while points of co-localization of the AnxA1 protein and NLRP3 inflammasome were detected in WT cells, as demonstrated by ultrastructural analysis. The lipidomic analysis showed a pronounced release of prostaglandins in nigericin-stimulated WT peritoneal macrophages, while ceramides were detected in AnxA1 -/cell supernatants. Different eicosanoid profiles were detected for both genotypes, and our results suggest that endogenous AnxA1 regulates the NLRP3-derived IL-1β and lipid mediator release in macrophages.

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Metabolic regulation of NLRP3

Cited by 241 publications

References 89 publications

Anti-TLR2 antibody triggers oxidative phosphorylation in microglia and increases phagocytosis of β-amyloid

Anti-TLR2 antibody triggers oxidative phosphorylation in microglia and increases phagocytosis of β-amyloid

Caspase 1 activity influences juvenile Batten disease (CLN3) pathogenesis

Annexin A1 Regulates NLRP3 Inflammasome Activation and Modifies Lipid Release Profile in Isolated Peritoneal Macrophages

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